Highly chemoselective lithium metal reductions of benzaldehyde bis(2-methoxyethyl) acetals

Article abstract of DOI:10.1002/1099-0690(200211)2002:22<3833::AID-EJOC3833>3.0.CO;2-K

Naphthalene-catalysed reductions of PhCH(OR)₂ (R = Me, CH₂CH₂OMe) acetals by lithium metal, followed by reactions with electrophiles (H₊, TMSCl, nBuBr, CH₂=CHCH₂Br), proceed with high chemoselectivity when the reductions are carried out at -90 °C especially for R = CH₂CH₂OMe. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany 2002.

Full text of DOI:10.1002/1099-0690(200211)2002:22<3833::AID-EJOC3833>3.0.CO;2-K

FULL PAPER
Highly Chemoselective Lithium Metal Reductions of Benzaldehyde
Bis(2-Methoxyethyl) Acetals
Thomas von Schrader[a] and Simon Woodward*[a]
Keywords: Synthetic methods / Lithiation / Reduction / Electron transfer / Alkylation
Naphthalene-catalysed reductions of PhCH(OR)2 (R = Me,
CH2CH2OMe) acetals by lithium metal, followed by reac- 2002)
tions with electrophiles (H+, TMSCl, nBuBr, CH2=CHCH2Br),
proceed with high chemoselectivity when the reductions are
carried out at −90 °C especially for R = CH2CH2OMe.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
Introduction
Lithium naphthalenide (LiC10H8) is a well-known, ex-
tremely potent, stoichiometric reagent (E0 ϭ Ϫ2.50 V vs.
SCE) that participates in many single- and multiple-electron
reductions.[1] In recent years there has been an upturn in
the interest in equivalent reactions using catalytic amounts
of naphthalene (and related electron-transfer catalysts) in
the presence of lithium powder as the terminal reductant.[1]
Naphthalenide-promoted cleavages of CϪO bonds with
stoichiometric MC10H8 (M ϭ Li, Na) were first described
Scheme 1. Reduction of aromatic acetals
in the 1960s.[1a] This paper is concerned with catalytic CϪO
cleavage reactions of acetals and related species (derived ion.[6] Subsequent reaction with electrophiles (Eϩ) are also
from benzaldehyde), chemistry first developed by Yus, Az- known to proceed with either retention or inversion de-
zena and co-workers.[2Ϫ4] Typical behaviour for these reac- pending on Eϩ.[7] If appropriate conditions could be identi-
tions is shown in Scheme 1. Stepwise addition of two elec- fied whereby the organolithium compounds 2 could be at-
trons to 1 results in organolithium compound 2 with con- tained with high enantiomeric purity, and subsequently
comitant formation of 1 equiv. of LiOR. The presence of trapped in a controlled manner with Eϩ, then useful new
these alkoxide by-products has been proposed[3] to stabilise methodology would result. This major challenge requires
2 against [1,2]-Wittig rearrangement[5] allowing interception selective enantiotopic CϪOR cleavage on addition of the
of 1 with suitable electrophiles (HX, TMSCl, RX, etc.) at second electron to radical anion A or subsequent kinetic
relatively high temperatures (typically Ϫ40 °C to room tem- resolution of the species 2. Some success has been attained
perature). In general, however, while these reactions do pro- in the reduction of the arenetricarbonylchromium acetal 4
vide the desired target molecules the chemistry is rather with a stoichiometric amount of lithium 4,4Ј-di(tert-butyl)-
prone to by-product formation or double reduction.[3]
biphenyl, followed by TMSCl addition, where an 88% de is
Additionally, there are interesting stereochemical issues attained.[8] However, equivalent catalytic approaches re-
in this reduction chemistry. The organolithium compounds main quite undeveloped.[9] As an initial goal towards this
2 contain a chiral centre but as a consequence of the achiral challenging ideal we have focused on identifying reliable
LiC10H8 reduction is, of course, obtained as a racemic mix- conditions whereby aromatic acetals 1 undergo both reduct-
ture. The configurational stability of such organolithium ive cleavage and subsequent reaction with electrophiles with
species is known to be a function of its method of prepara- very high chemoselectivity.
tion, the solvent and any ligands coordinating the lithium
[a]
School of Chemistry, The University of Nottingham,
University Park,
Nottingham NG7 2RD, United Kingdom
Fax: (internat.) ϩ 44-115/951-3564
E-mail: simon.woodward@nottingham.ac.uk
Eur. J. Org. Chem. 2002, 3833Ϫ3836  2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1122Ϫ3833 $ 20.00ϩ.50/0
3833

T. von Schrader, S. Woodward
FULL PAPER
low temperature could be improved by use of suitable che-
late groups built into the acetal substrate 1. 6-Phenyl-
2,5,7,10-tetraoxaundecane (1b) was found to be the best.
For example, when 1b was exposed to 7 mol % naphthalene
at Ϫ90 °C, in the presence of 4Ϫ4.5 equiv. of lithium pow-
der extremely clean reduction in just 4Ϫ6 h was realised, as
evidenced by quenching with water. At these low temper-
atures no CIPE-induced elimination occurs and 5 may be
intercepted by a range of electrophiles (Table 2).
Results and Discussion
In our hands, reduction of THF solutions of (dimethoxy-
methyl)benzene (1a) (R ϭ Me) with 2.8 equiv. of lithium
powder, under literature conditions,[3] under argon at Ϫ40
°C using 10 mol % C10H8 followed by alkylation with
nBuBr resulted in only partial consumption of 1a and the
formation of a product mixture. Aside from the desired
product 3a (E ϭ Bu) and small amounts of 3a (E ϭ H),
resulting from adventitious reaction of 2a with protons,
traces of [1,2]-Wittig rearrangement products and benzyl al-
Table 2. C10H8-catalysed reduction of 6-phenyl-2,5,7,10-tetra-
oxaundecane (1b) at Ϫ90 °C with lithium followed by reaction
with electrophiles
cohol were detected. In reductions of 1b (R
ϭ
CH2CH2OMe), at Ϫ40 °C, employing either extended reac-
tion times or increased equivalents of lithium gave, after
quenching with water, benzyl alcohol as the major product.
The latter behaviour implies a rapid intramolecular ‘‘com-
plex-induced proximity effect’’ (CIPE)[10] via 5. Consistent
with this suggestion attempts to intercept 5, under these
conditions, with TMSCl or D2O were unsuccessful and use
of [D8]THF as solvent did not lead to deuterium incorpora-
tion into the product benzyl alcohol. However, in no case
was overreduction to toluene observed.
Run Eϩ
Equiv. Conditions
Yield 3b/%[a]
1
2
3
H2CϭCHCH2Br
H2CϭCHCH2Br
NBuBr
1.6
2
40 min, Ϫ90 °C 66
20 min, Ϫ90 °C 75
1.6
2
40 min, Ϫ90 °C 72
20 min, Ϫ90 °C 89
4
NBuBr
5
TMSCl
3
20 min, Ϫ90 °C 90
6
7
8
9
tBuCHO
PhCHO
cyclohexanone
H2O
2
2
2
Ͼ 5
20 min, Ϫ90 °C 78 (syn/anti ϭ 2:1)
20 min, Ϫ90 °C 62 (syn/anti ϭ 3:1)
20 min, Ϫ90 °C 86
20 min, Ϫ90 °C 90
10
11
[D3]MeOD
MeOC(ϭO)Cl
Ͼ 5
5
20 min, Ϫ90 °C 91
20 min, Ϫ90 °C 17 (with 57% 6)
The difficulties of attaining clean reactions under such
conditions are hinted at in the literature where low or
NMR-estimated yields are frequently reported.[2Ϫ4] We
considered that by lowering the reaction temperature would
significantly improve the stability of the reduction interme-
diates and thus improve the chemoselectivity. Typical results
are shown in Table 1.
[a]
Isolated yield. Reduction conditions: 1b (0.17  in THF), 4Ϫ4.5
equiv. Li, 7Ϫ8 mol % naphthalene (Ϫ90 °C, 6 h). After reaction
with the electrophile, the mixture was quenched with water and
warmed up.
Although cleaner, these reductions proceeded rather
slowly even though a significant excess of terminal lithium
was used (Runs 1Ϫ3). Attempts to further promote the re-
action by (Ϫ)-sparteine as a polar additive (200 mol %)
Proton NMR spectra of the crude reaction products
were unsuccessful Ϫ the reaction slowed and only racemic (Runs 1Ϫ10) revealed only the presence of the desired prod-
3a (E ϭ allyl) was attained in reduced yield (Run 3). No uct 3b, residual electrophile and traces of naphthalene in all
reduction was observed in diethyl ether (Ϫ 40 °C); difficulty cases except methyl chloroformate (Run 11). For the latter,
in generating lithium naphthalenide in the absence of THF double addition of the anion leads to the formation of 6 as
is known. We believed that the efficiency of the reaction at the major product even when excess chloroformate is used.
Table 1. C10H8-catalysed reduction of (dimethoxymethyl)benzene (1a) at Ϫ90 °C with lithium followed by reaction with electrophiles
Run
Solvent
Conc. 1a/ (equiv. Li)
C10H8/mol %
(time/h)
Eϩ (conditions)
Yield/%[a]
1
2
3
THF
THF
THF
0.17 (4.7)
0.17 (5.1)
0.23 (4.7)
8 (23)
H2CϭCHCH2Br (20 min, Ϫ90 °)
BuBr (20 min, Ϫ90 °)
H2CϭCHCH2Br (20 min, Ϫ90 °)
69
7 (23)
81
7 (23)[b]
53[c]
[a]
1
[b]
[c]
Isolated yield, sole product by H NMR on crude material. 200 mol % (Ϫ)-sparteine added. Ͻ 2% ee.
3834
Eur. J. Org. Chem. 2002, 3833Ϫ3836

Highly Chemoselective Lithium Metal Reductions of Benzaldehyde Bis(2-Methoxyethyl) Acetals
FULL PAPER
1
Yield 10.0 g, 85%. H NMR (CDCl3, 400 MHz): δ ϭ 3.39 (s, 6 H,
2 ϫ OMe), 3.55Ϫ3.57 (m, 4 H, 2 ϫ OCH2), 3.58Ϫ3.72 (m, 4 H, 2
ϫ OCH2), 5.69 (s, 1 H, PhCH), 7.29Ϫ7. 38 (m, 3 H, CH-arom.),
7.50Ϫ7.52 (m, 2 H, CH-arom.). 13C NMR (CDCl3, 67.8 MHz):
δ ϭ 58.5 (OMe), 63.7 (OCH2), 71.4 (OCH2), 101.0 (PhCH), 126.4
(CH), 127.7 (CH), 127.9 (CH), 137.8 (Cq) ppm. IR (thin film): ν˜ ϭ
2926 s, 2877 s, 1451 m, 1104 s, 1063 s cmϪ1. MS (EI): m/z (%) ϭ
240 (1.5) [Mϩ], 165 (100), 59 (98). HRMS, EI: calcd. for C13H20O4
[Mϩ] 240.1361; found 240.1359.
In condensation of 2b with aldehydes some modest diaster-
eoselectivity was realised (Runs 6Ϫ7).
Potentially, the chelating nature of 2b and the very low
temperatures used in these preparations should increase the
configurational stability of the stereogenic centre. Such ap-
proaches have proved highly successful in the preparations
of chiral organolithium compounds by deprotonation strat-
egies in the presence of chiral additives.[11] However, these
deprotonations are normally carried out in diethyl ether or
other low-polarity solvents and these are known to strongly
inhibit naphthalene-catalysed reductions by lithium. Using
naphthalene (15 mol %) as the sole catalyst and an increas-
ing volume fraction of diethyl ether in an Et2O/THF mix-
ture for the reduction of 1b with lithium (6 equiv.) leads to
a gradual reduction in the reaction efficiency. At a 5:1 Et2O/
THF mixture no reduction is observed. Similar effects are
noted for DME/Et2O mixtures. Because of the very mild
conditions associated with this route some chiral additives
(binaphthalenes, chiral diamides and oxazolines) bearing
pendent naphthalene units were screened, but no significant
asymmetric induction was realised.
General Procedure for the Reductions: To a stirred suspension of Li
(4Ϫ4.5 equiv.) in 3 mL of THF was added naphthalene (10 mg, 7
mol %) at room temp. After obtaining a dark green colour, the
mixture was diluted with 3 mL of THF and cooled to Ϫ90 °C. The
acetal (1 mmol) was added dropwise and stirring was continued for
6 h (1b) or 23 h (1a). The corresponding electrophiles (2Ϫ5 equiv.)
were added and the mixture was stirred for 20 min at the same
temperature. The reaction mixture was quenched with half-satur-
ated NH4Cl, warmed up to room temperature and worked up as
usual. The resulting crude products were purified by flash chroma-
tography [petroleum ether (b.p. 40Ϫ60 °C)/diethyl ether, 3:1Ϫ2:1].
(1-Methoxybut-3-enyl)benzene (3a, E ؍ CH2CH؍CH2):[12] Yield
115 mg, 69%. 1H NMR (CDCl3, 400 MHz): δ ϭ 2.44 (dddt, J ϭ
14, 8, 6, 1.5 Hz, 1 H), 2.58 (dddt, J ϭ 14, 7, 6, 1.5 Hz, 1 H), 3.25
(s, 3 H, OMe), 4.17 (dd, J ϭ 8, 7 Hz, 1 H, PhCH), 5.04 (ddt, J ϭ
11, 2, 1.5 Hz, 1 H, ϭCH2), 5.08 (ddt, J ϭ 17, 2, 1.5 Hz, 1 H, ϭ
CH2), 5.70 (ddt, J ϭ 17, 11, 6 Hz, 1 H, ϭCH), 7.27Ϫ7.41 (m, 5 H,
CH-arom.) ppm. 13C NMR (CDCl3, 100.6 MHz): δ ϭ 42.4 (CH2),
56.6 (OMe), 83.6 (PhCH), 116.8 (ϭCH2), 126.7 (CH), 127.5 (CH),
128.3 (CH), 134.7 (ϭCH), 141.6 (Cq) ppm. IR (thin film): ν˜ ϭ 2979
Conclusion
Approaches to improving the chemoselectivity in naph-
thalene-catalysed reduction of aromatic acetals have been
developed. Both the use of low temperature reduction con-
ditions and employing substrates containing chelate func-
tions improve the utility of the reaction and together these
fashion final alkylated products cleanly.
m, 2935 m, 2820 m, 1454 m, 1100 s, 701 s cmϪ1
.
(1-Methoxypentyl)benzene (3a, E ؍ nBu):[12] Yield 144 mg, 81%. 1H
NMR (CDCl3, 400 MHz): δ ϭ 0.89 (t, J ϭ 7 Hz, 3 H, CH2Me),
1.20Ϫ1.43 (m, 4 H), 1.58Ϫ1.68 (m, 1 H), 1.77Ϫ1.87 (m, 1 H), 3.22
(s, 3 H, OMe), 4.10 (dd, J ϭ 7, 6 Hz, 1 H, PhCH), 7.27Ϫ7.38 (m,
5 H, CH-arom.) ppm. 13C NMR (CDCl3, 100.6 MHz): δ ϭ 13.9
(CH2Me), 22.6 (CH2), 27.9 (CH2), 37.8 (CH2), 56.5 (OMe), 84.1
(PhCH), 126.6 (CH), 127.3 (CH), 128.2 (CH), 142.5 (Cq) ppm. IR
Experimental Section
(thin film): ν˜ ϭ 2956 s, 2932 s, 2859 m, 1453 m, 1097 s cmϪ1
.
General: Infrared spectra were recorded using a Nicolet Avatar 320
FT-IR infrared spectrophotometer. 1H and 13C NMR spectra were
recorded with Bruker (AM, 400, AV 400) and JEOL 270 spectro-
meters at ambient temperature using tetramethylsilane as standard;
J values are given in Hz. Mass spectra were obtained with a VG
Autospec or Micromass 70 E (electron impact, EI, 70 eV) mass
spectrometer. CI (NH3) and ES spectra were measured at the
EPSRC National Mass Spectrometry Service Centre, University of
Wales, Swansea. Melting points were recorded using a Mel-Temp
II and are not corrected. Tetrahydrofuran (THF) and diethyl ether
were distilled from Na/benzophenone under argon. Catalytic reac-
tions were carried out under argon using standard Schlenk tech-
niques. Column chromatography and TLC analyses were per-
formed on silica gel Prola 60, 35Ϫ75 µm (200Ϫ400 mesh) and
Merck aluminium sheets 60 F254, respectively. Lithium powder
(Merck Eurolab) and all other reagents were used as supplied.
Compound 1a is commercial (Lancaster Synthesis).
[(2-Methoxyethoxy)phenylmethyl]trimethylsilane (3b, E ؍ TMS):
Yield 215 mg, 90%. H NMR (CDCl3, 400 MHz): δ ϭ Ϫ0.57 (s, 9
1
H, SiMe3), 3.34Ϫ3.39 (m, 1 H, OCH2), 3.38 (s, 3 H, OMe),
3.50Ϫ3.60 (m, 2 H, OCH2), 3.68Ϫ3.73 (m, 1 H, OCH2), 4.11 (s, 1
H, PhCH), 7.14Ϫ7.18 (m, 3 H, CH-arom.), 7.26Ϫ7.31 (m, 2 H,
CH-arom.) ppm. 13C NMR (CDCl3, 100.6 MHz): δ ϭ Ϫ4.0
(SiMe3), 59.0 (OMe), 70.4 (OCH2), 72.1 (OCH2), 78.8 (CH), 125.5
(CH), 125.7 (CH), 141.5 (Cq) ppm. IR (thin film): ν˜ ϭ 2955 m,
2898 m, 1247 s, 1088 s, 869 s, 840 s cmϪ1. MS (CI): m/z (%) ϭ 256
(52) [Mϩ ϩ NH4], 179 (100). HRMS, ES: calcd. for C13H26NO2Si
[M ϩ NH4ϩ] 256.1733, found 256.1735.
1-(2-Methoxyethoxy)-3,3-dimethyl-1-phenylbutan-2-ol (3b,
E
؍
Me3CCHOH): Yield 197 mg, 78% (syn/anti ϭ 2:1). 1H NMR
(CDCl3, 400 MHz): δ ϭ 0.90 (s, 9 H, tBu, syn), 0.94 (s, 9 H, tBu,
anti), 3.34 (s, 3 H, OMe), 3.38Ϫ3.59 (m, 5 H), 4.30 (d, J ϭ 7 Hz, 1
H, PhCH), 4.35 (d, J ϭ 4 Hz, 1 H, PhCH), 7.27Ϫ7.41 (m, 5 H, CH-
arom.) ppm. 13C NMR (CDCl3, 100.6 MHz) ϭ 26.5 (tBu), [34.4,
34.7] (CMe3), 58.6 (OMe) [67.3, 67.4] (OCH2), [71.6, 71.7] (OCH2),
[80.3, 81.3] (OCH), [81.9, 83.4] (OCH), 127.2 (CH), 127.6 (CH),
127.9 (CH), 128.1 (CH), 128.2 (CH), 128.4 (CH), [139.4, 140.7] (Cq)
ppm. IR (thin film): ν˜ ϭ 3457 (OH), 2952 s, 2871 s, 1453 m, 1094 s
cmϪ1. MS (CI): m/z (%) ϭ 270 (80) [Mϩ ϩ NH4], 193 (100). HRMS,
ES: calcd. for C15H28NO3 [Mϩ ϩ NH4] 270.2069, found 270.2067.
Substrate Preparations
6-Phenyl-2,5,7,10-tetraoxaundecane (1b): This compound was pre-
pared using standard techniques (DeanϪStark trap);
5 mL
(49.3 mmol) of benzaldehyde and 20 mL of methoxyethanol were
solved in 70 mL of benzene and a catalytic amount (300 mg) of
para-toluenesulfonic acid was added. After usual workup, the crude
product was purified by bulb-to-bulb distillation (150Ϫ160 °C)0.7
.
Eur. J. Org. Chem. 2002, 3833Ϫ3836
3835

T. von Schrader, S. Woodward
FULL PAPER
1-[(2-Methoxyethoxy)phenylmethyl]cyclohexanol
C(CH2)5(OH)]: Yield 227 mg, 86%. H NMR (CDCl3, 400 MHz): (dd, J ϭ 7, 6 Hz, PhCH), 7.25 Ϫ7.38 (m, 5 H, CH-arom.) ppm.
δ ϭ 1.0Ϫ1.8 (m, 11 H), 2.46 (br. s, 1 H), 3.37 (s, 3 H, OMe),
[3b,
E
؍
1 H), 3.37 (s, 3 H, OMe), 3.38Ϫ3.55 (m, 4 H, 2 ϫ OCH2), 4.20
1
13C NMR (CDCl3, 67.8 MHz): δ ϭ 13.9 (CH2Me), 22.5 (CH2),
3.4Ϫ3.63 (m, 4 H, 2 ϫ OCH2) 4.11 (s, 1 H, PhCH), 7.28Ϫ7.40 (m, 27.9 (CH2), 37.9 (CH2), 58.8 (OMe), 67.8 (OCH2), 71.9 (OCH2),
5 H, CH-arom.) ppm. 13C NMR (CDCl3, 67.8 MHz): δ ϭ 21.2 82.8 (PhCH), 126.6 (CH), 127.2 (CH), 128.2 (CH), 142.7 (Cq) ppm.
(CH2), 21.4 (CH2), 25.7 (CH2), 31.8 (CH2), 34.0 (CH2), 58.7 IR (thin film): ν˜ ϭ 2930 s, 2886 s, 1452 m, 1099 s cmϪ1. MS (EI):
(OMe), 68.5 (OCH2), 71.7 (OCH2), 73.2 (Cq), 89.2 (CH), 127.5 m/z (%) ϭ 222 (3) [Mϩ], 165 (100), 91 (39), 59 (59). HRMS, EI:
(CH), 127.7 (CH), 128.3 (CH), 138.0 (Cq) ppm. IR (thin film): ν˜ ϭ
3453 (OH), 2930 s, 2859 s, 1450 s, 1093 s cmϪ1. MS (EI): m/z (%) ϭ
264 (10) [Mϩ], 247 (100). HRMS, EI: calcd. for C16H24O3 [Mϩ]
264.1725, found 264.1726.
calcd. for C14H22O2 [Mϩ] 222.1620, found 222.1627.
Methyl 2-(2-Methoxyethoxy)-2-phenylacetate (3b, E ؍ CO2Me):
1
Yield 38 mg, 17%. H NMR (CDCl3, 400 MHz): δ ϭ 3.37 (s, 3 H,
OMe), 3.59Ϫ3.71 (m, 4 H, 2 ϫ OCH2), 3.72 (s, 3 H, COOMe), 4.99
(s, 1 H, PhCH), 7.33Ϫ7.38 (m, 3 H, CH-arom.), 7.45Ϫ7.47 (m, 2 H,
CH-arom.) ppm. 13C NMR (CDCl3, 100.6 MHz): δ ϭ 52.1 (CO-
OMe), 58.9 (OMe), 68.9 (OCH2), 71.8 (OCH2), 81.3 (PhCH), 127.2
(CH), 128.5 (CH), 128.6 (CH), 136.3 (Cq), 171.2 (COOMe) ppm. IR
(thin film): ν˜ ϭ 2926 m, 2880 m, 1751 s (CϭO), 1113 s cmϪ1. MS
(EI): m/z (%) ϭ 224 (4) [Mϩ], 165 (100), 59 (96). HRMS, EI: calcd.
for C12H16O4 [Mϩ] 224.1048, found 224.1043.
2-(2-Methoxyethoxy)-1,2-diphenylethanol [3b, E ؍ CHC6H4(OH)]:
1
Yield 169 mg, 62% (syn/anti ϭ 3:1). H NMR (CDCl3, 400 MHz):
syn: δ ϭ 2.85 (d, J ϭ 4 Hz, 1 H, OH), 3.34 (s, 3 H, OMe), 3.40Ϫ3.70
(m, 4 H, 2 ϫ OCH2), 4.54 (d, J ϭ 5 Hz, 1 H, PhCH), 4.96 (dd, J ϭ
5, 4 Hz, 1 H, PhCH), 7.11Ϫ7.27 (m, 10 H, CH-arom.) ppm. anti:
3.41 (s, 3 H, OMe), 3.49Ϫ3.86 (m, 4 H, 2 ϫ OCH2) 3.86 (s, 1 H,
OH), 4.25 (d, J ϭ 9 Hz, PhCH), 4.69 (d, J ϭ 9 Hz, PhCH),
6.99Ϫ7.05 (m, 4 H, CH-arom.), 7.15Ϫ7.22 (m, 6 H, CH-arom.) ppm.
13C NMR (CDCl3, 100.6 MHz): syn: δ ϭ 58.7 (OMe), 68.3 (OCH2),
71.7 (OCH2), 76.6 (CH), 86.2 (CH), 126.9 (CH), 127.1 (CH), 127.5
(CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 137.4 (Cq), 140.1 (Cq)
ppm. anti: 13C NMR (CDCl3, 67.8 MHz): δ ϭ 58.9 (OMe), 68.4
(OCH2), 71.7 (OCH2), 78.6 (CH), 88.3 (CH), 127.3 (CH), 127.60
(CH), 127.65 (CH), 127.7 (CH), 127.9 (CH), 137.0 (Cq), 139.1 (Cq)
ppm. IR (thin film): ν˜ ϭ 3431 (OH), 3030 m, 2877 s, 1452 s, 1092 s
cmϪ1. MS (CI): m/z (%) ϭ 290 (100) [Mϩ ϩ NH4], 272 (35) [Mϩ],
255 (36), 213 (22). HRMS, ES: calcd. for C17H24NO3 [Mϩ ϩ NH4]
290.1756, found 290.1754.
6,8-Diphenyl-2,5,9,12-tetraoxatridecan-7-one (6): Yield 204 mg,
1
57%. H NMR (CDCl3, 400 MHz): δ ϭ 3.30 (s, 3 H, OMe), 3.32
(s, 3 H, OMe), 3.35Ϫ3.58 (m, 8 H, 4 ϫ OCH2), 5.15 (s, 2 H, 2 ϫ
PhCH), 7.17Ϫ7.42 (m, 10 H, CH-arom.) ppm. 13C NMR (CDCl3,
100.6 MHz): δ ϭ 58.8 (OMe), [68.4, 68.5] (OCH2), [71.6, 71.7]
(OCH2), 84.7 (PhCH), 128.03 (CH), 128.09 (CH), 128.4 (CH),
[135.3, 135.6] (Cq), [203.9, 204.3] (CϭO) ppm. IR (thin film): ν˜ ϭ
2924 m, 2876 m, 1731 s (CϭO), 1453 m, 1109 s cmϪ1. MS (CI): m/
z (%) ϭ 376 (100) [Mϩ ϩ NH4], 302 (78), 228 (25), 164 (40).
HRMS, ES: calcd. for C21H30NO5 [Mϩ ϩ NH4] 376.2124, found
376.2123.
[(2-Methoxyethoxy)methyl]benzene (3b, E ؍ H):[13] Yield 149 mg,
90%. 1H NMR (CDCl3, 400 MHz): δ ϭ 3.40 (s, 3 H, OMe),
3.57Ϫ3.64 (m, 4 H, 2 ϫ OCH2), 4.58 (s, 2 H, PhCH2), 7.28Ϫ7.36
(m, 5 H, CH-arom.) ppm. 13C NMR (CDCl3, 67.8 MHz): δ ϭ 58.8
(OMe), 69.1 (OCH2), 71.8 (OCH2), 73.1 (PhCH2), 127.4 (CH),
127.6 (CH), 128.1 (CH), 138.0 (Cq) ppm. IR (thin film): ν˜ ϭ 2873
Acknowledgments
We thank the Leverhulme Trust for a Fellowship to T. v. S.
(through grant A/20000306) and the EPSRC Mass Spectrometry
Service for access to its facilities.
m, 1453 m, 1102 s cmϪ1
.
[1]
Reviews: [1a] N. L. Holy, Chem. Rev. 1974, 74, 243Ϫ277. [1b] D.
[α-D][2-(Methoxyethoxy)methyl]benzene (3b, E ؍ D): Yield 152 mg,
91%. 1H NMR (CDCl3, 400 MHz): δ ϭ 3.41 (s, 3 H, OMe),
3.57Ϫ3.65 (m, 4 H, 2 ϫ OCH2), 4.56 (t, J ϭ 1.6 Hz, 1 H, PhCHD),
´
J. Ramon, M. Yus, Eur. J. Org. Chem. 2000, 225Ϫ237.
[2]
[3]
´
J. F. Gil, D. J. Ramon, M. Yus, Tetrahedron 1993, 49,
9535Ϫ9546.
7.28Ϫ7.36 (m,
5
H, CH-arom.) ppm. 13C NMR (CDCl3,
U. Azzena, G. Melloni, L. Pisano, B. Sechi, Tetrahedron Lett.
1994, 35, 6759Ϫ6762.
U. Azzena, L. Pilo, E. Piras, Tetrahedron 2000, 56, 3775Ϫ3780.
U. Schöllkopf, Angew. Chem. Int. Ed. Engl. 1970, 9, 763Ϫ773.
Reviews: D. Hoppe, T. Hense, Angew. Chem. Int. Ed. Engl.
1997, 36, 2282Ϫ2316.
100.6 MHz): δ ϭ 58.9 (OMe), 69.1 (OCH2), 71.8 (OCH2), [72.5,
72.8, 73.0] (PhCHD), 127.4 (CH), 127.6 (CH), 128.2 (CH), 138.0
(Cq) ppm. IR (thin film): ν˜ ϭ 2874 m, 1451 m, 1108 s cmϪ1. MS
(EI): m/z (%) ϭ 167 (41) [Mϩ], 108 (30), 92 (100). HRMS, EI:
calcd. for C10H13DO2 [Mϩ] 167.1056, found 167.1056.
[4]
[5]
[6]
[7]
F. Hammerschmidt, A. Hanninger, B. P. Simov, H. Völlenkle,
A. Werner, Eur. J. Org. Chem. 1999, 3511Ϫ3518.
M. J. Siwek, J. R. Green, Synlett 1996, 560Ϫ562.
For an alternative approach using BF3·OEt2 activation of acet-
als in the presence of chiral lithium reagents, see: P. Müller, P.
Nury, Org. Lett. 2000, 2, 2845Ϫ2847.
[1-(2-Methoxyethoxy)but-3-enyl]benzene (3b, E ؍ CH2CH؍CH2):
1
[8]
[9]
Yield 156 mg, 75%. H NMR (CDCl3, 400 MHz): δ ϭ 2.42 (dddt,
J ϭ 14, 7, 6, 1.5 Hz, 1 H), 2.64 (dddt, J ϭ 14, 7, 7, 1.5 Hz, 1 H),
3.37 (s, 3 H, OMe), 3.40Ϫ3.60 (m, 4 H, 2 ϫ OCH2), 4.30 (dd, J ϭ
7, 6 Hz, 1 H, PhCH), 5.01 (ddt, J ϭ 10, 2, 1.5 Hz, 1 H, ϭCH2),
5.04 (ddt, J ϭ 17, 2, 1.5 Hz, 1 H, ϭCH2), 5.77 (ddt, J ϭ 17, 10,
7 Hz, 1 H, ϭCH), 7.25Ϫ7.38 (m, 5 H, CH-arom.) ppm. 13C NMR
(CDCl3, 67.8 MHz): δ ϭ 42.4 (CH2), 58.8 (OMe), 67.8 (OCH2),
71.8 (OCH2), 82.4 (PhCH), 116.7 (ϭCH2), 126.6 (CH), 127.4 (CH),
128.2 (CH), 134.6 (ϭCH), 141.7 (Cq) ppm. IR (thin film): ν˜ ϭ 2873
[10]
[11]
P. Beak, A. I. Meyers, Acc. Chem. Res. 1986, 19, 356Ϫ353.
[11a]
For recent examples see:
D. J. Pippel, G. A. Weisenburger,
N. C. Faibish, P. Beak, J. Am. Chem. Soc. 2001, 123,
[11b]
4919Ϫ4927.
Lett. 2000, 2, 875Ϫ878.
Hoppe, Chem. Eur. J. 1999, 5, 3459Ϫ3463.
X. Li, L. B. Schenkel, M. C. Kozlowski, Org.
[11c]
E.-U. Würthwein, K. Behrens, D.
[11d]
Y. S. P a r k , M .
m, 1452 m, 1100 s cmϪ1. MS (CI): m/z (%) ϭ 224 (65) [Mϩ
ϩ
L. Boys, P. Beak, J. Am. Chem. Soc. 1996, 118, 3757Ϫ3758.
J. J. Gajewski, W. Bocian, N. J. Harris, L. P. Olson, J. P. Gajew-
ski, J. Am. Chem. Soc. 1999, 121, 326Ϫ334.
M. Sheehan, R. J. Spangler, C. Djerassi, J. Org. Chem. 1971,
36, 3526Ϫ3532.
[12]
[13]
NH4], 147.9 (22), 130 (100). HRMS, ES: calcd. for C13H22NO2
[Mϩ ϩ NH4] 224.1651, found 224.1658.
[1-(2-Methoxyethoxy)pentyl]benzene (3b, E ؍ nBu): Yield 198 mg,
89%. 1H NMR (CDCl3, 400 MHz): δ ϭ 0.87 (t, J ϭ 7 Hz, 3 H,
CH2Me), 1.15Ϫ1.45 (m, 4 H), 1.58Ϫ1.68 (m, 1 H), 1.81Ϫ1.92 (m,
Received June 11, 2002
[O02312]
3836
Eur. J. Org. Chem. 2002, 3833Ϫ3836